Individuals affected with tuberous sclerosis complex (TSC) develop subependymal giant cell astrocytomas, suggesting that the TSC gene products, hamartin and tuberin, function as a negative growth regulators for astrocytes. In this proposal, we plan to critically test the hypothesis that hamartin and tuberin regulate astrocyte growth and prevent astrocytoma formation. Previously, we have demonstrated that loss of tuberin is associated with brain tumor formation and that both reduced expression of tuberin and hamartin result in increased astrocyte growth in vivo. Specifically, we plan to determine whether (1) absent TSC expression is astrocytes results in increased astrocyte proliferation and tumor formation in vitro and in vivo and (2) tuberin and hamartin regulate astrocyte cell growth in a rap 1- and p27-Kipl-dependent fashion. These studies are aimed at understanding how tuberin and hamartin function as growth regulators for astrocytes relevant to tumor formation.